P32 MAJESTEC-1: CORRELATIVE ANALYSES OF TECLISTAMAB, A B-CELL MATURATION ANTIGEN (BCMA) X CD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM)
Authors: N. van de Donk, D. Cortes-Selva, T. Casneuf, D. Vishwamitra, S. Stein, T. Perova, E. Ramos, L. Van Steenbergen, R. Boominathan, O. Lau, C. Davis, A. Banerjee, T. Stephenson, C. Uhlar, R. Kobos, J. Goldberg, L. Pei, D. Trancucci, S. Girgis, S.X.W. Lin, L.S. Wu, P. Moreau, S. Usmani, N.J. Bahlis, R. Verona
Journal: HemaSphere (2023)

Introduction: Teclistamab, a BCMA bispecific IgG4 antibody, redirects CD3+ T cells to mediate T cell activation and subsequent BCMA-expressing myeloma cell lysis. MajesTEC-1, a multicohort, open-label, phase 1/2 study, investigated teclistamab safety/efficacy in patients (pts) with RRMM previously receiving ≥3 lines of therapy. In phase 1, recommended phase 2 dose (RP2D) of teclistamab was 1.5mg/kg subcutaneous (SC) once weekly, preceded by 0.06 and 0.3mg/kg step-up doses. Initial results of RP2D-treated pts in phase 1/2 (no prior BCMA-targeted treatment exposure) demonstrated teclistamab was well tolerated with encouraging efficacy. Here, we report translational research data from MajesTEC-1 of the pivotal RP2D and active dose pt cohorts. Methods: Baseline/on-treatment whole blood and bone marrow aspirate samples from pivotal RP2D pts (SC) were analyzed by flow cytometry for BCMA expression/immune populations; serum samples were analyzed for soluble BCMA (sBCMA) by electrochemiluminescence ligand binding, and cytokines by MSD/Luminex assays; whole blood from active dose cohorts (intravenous/SC) was analyzed by cytometry by time of flight (CyTOF). Results: Baseline BCMA expression on bone marrow plasma cells was prevalent and highly variable among pts with RRMM but not associated with clinical responses to teclistamab; higher baseline sBCMA levels associated with lower response rates and high-risk disease characteristics (higher revised International Staging System stage, high bone marrow plasma cells [>60%], extramedullary plasmacytoma presence). Nonresponders had lower peripheral CD8 T cell counts, higher regulatory T cells (Tregs) and CD38+ Tregs, higher overall T cells expressing PD-1, TIM-3, CD38 in peripheral blood and bone marrow at baseline. Baseline analysis also showed enhancement of a naïve phenotype in T cells in responders. Higher baseline T cells expressing PD-1, TIM-3, CD38, CD25, PD-1/TIM-3, PD-1/CD38 observed in blood and bone marrow of pts with high bone marrow plasma cells (>60%), high composite tumor score (plasmacytosis ≥80%, serum M-spike ≥5g/dL, serum free light chain ≥5000 mg/L). Shorter progression-free survival (PFS) was associated with higher peripheral PD-1+ CD8 and baseline Tregs. Higher baseline CD25+ CD4, CD38+ CD4 bone marrow T cells correlated with lower PFS after tumor burden adjusting. Baseline T cell profile associated with worse clinical outcome likely reflects dysfunctional and exhausted T cell phenotype. Accordingly, lower interferon-g and PD-1+ CD8, CD25+ CD4, CD38+ CD4 T cell induction was observed with teclistamab treatment (nonresponders); teclistamab-mediated induction of peripheral PD‑1+ CD38+ CD8 T cells lower in pts with high tumor burden. Cytokine release syndrome was associated with higher CD3 T cells and lower baseline sBCMA, TIM-3, PD-1/TIM-3 expressing CD4 T cells in the periphery. Conclusions: Baseline correlative analysis for pivotal RP2D pts suggests emerging profile for nonresponders of unfavorable baseline immune characteristics, including lower T cell numbers, higher baseline T cells expressing PD-1, TIM-3, CD38, increased Tregs and CD38+ Tregs, and lower proportion of naïve T cells. These data support clinical combinations of teclistamab with agents like daratumumab or checkpoint inhibitors.